title: Targeting cell division cycle 25 homolog B to regulate influenza virus replication.
abstract: Influenza virus is a worldwide global health concern causing seasonal morbidity mortality and economic burden. Chemotherapeutics is available; however, rapid emergence of drug-resistant influenza virus strains has reduced its efficacy. Thus, there is a need to discover novel antiviral agents. In this study, RNA interference (RNAi) was used to screen host genes required for influenza virus replication. One pro-influenza virus host gene identified was dual-specificity phosphatase cell division cycle 25 B (CDC25B). RNAi screening of CDC25B resulted in reduced influenza A virus replication, and a CDC25B small-molecule inhibitor (NSC95397) inhibited influenza A virus replication in a dose-dependent fashion. Viral RNA synthesis was reduced by NSC95397 in favor of increased beta interferon (IFN-β) expression, and NSC95397 was found to interfere with nuclear localization and chromatin association of NS1, an influenza virus protein. As NS1 has been shown to be chromatin associated and to suppress host transcription, it is likely that CDC25B supports NS1 nuclear function to hijack host transcription machinery in favor of viral RNA synthesis, a process that is blocked by NSC95397. Importantly, NSC95397 treatment protects mice against lethal influenza virus challenge. The findings establish CDC25B as a pro-influenza A virus host factor that may be targeted as a novel influenza A therapeutic strategy.
authors.affiliation: University of Georgia College of Veterinary Medicine, Department of Infectious Diseases, Athens, Georgia, USA.
authors.forename: Olivia
authors.initials: O
authors.lastname: Perwitasari
authors.forename: Ana Claudia
authors.initials: AC
authors.lastname: Torrecilhas
authors.forename: Xiuzhen
authors.initials: X
authors.lastname: Yan
authors.forename: Scott
authors.initials: S
authors.lastname: Johnson
authors.forename: Caleb
authors.initials: C
authors.lastname: White
authors.forename: S Mark
authors.initials: SM
authors.lastname: Tompkins
authors.forename: Ralph A
authors.initials: RA
authors.lastname: Tripp
mesh_terms: D000818:Animals; D002460:Cell Line; D005260:Female; D018390:Gene Targeting; D054884:Host-Pathogen Interactions; D006801:Humans; D053118:Influenza A Virus, H1N1 Subtype / Q000235:genetics / Q000502:physiology*; D009981:Influenza B virus / Q000235:genetics / Q000502:physiology*; D007251:Influenza, Human / Q000201:enzymology* / Q000235:genetics / Q000821:virology; D016899:Interferon-beta / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D034622:RNA Interference; D014779:Virus Replication; D020687:cdc25 Phosphatases / Q000235:genetics* / Q000378:metabolism*
chemical_list: D016899:Interferon-beta; C517008:CDC25B protein, human; D020687:cdc25 Phosphatases